2-Decarboxy-2-tetrazolyl-6-alkoxy-PGI1 compounds

ABSTRACT

Prostacyclin I 1 , (PGI 1 ) derivatives and analogs having a 6-alkoxy feature and having pharmacological activity and processes for preparing them are disclosed.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Ser. No. 892,108, filedMar. 31, 1978, now U.S. Pat. No. 4,207,402.

BACKGROUND OF THE INVENTION

The present invention relates to novel2-decarboxy-2-tetrazolyl-6-alkoxy-PGI₁ compounds, useful aspharmaceutical agents, principally for the induction of certainprostacyclin-like pharmacological effects. The essential material ofconsisting description of the preparation and use of these substances isincorporated here by reference from Ser. No. 892,108, filed Mar. 31,1978, now U.S. Pat. No. 4,207,242.

SUMMARY OF THE INVENTION

The present invention particularly relates to a compound of formula 1##STR1## wherein L is

(1) --(CH₂)_(d) --C(R₂)₂ --,

(2) --(CH₂ --O--CH₂ --Y--, or

(3) --(CH₂ CH═CH--,

wherein d is zero to 5, R₂ is hydrogen, methyl or fluoro, being the sameor different with the proviso that one R₂ is not methyl when the otheris fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --;

wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈, wherein R₈ ishydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₄ is

(1) --C(R₅)(R₆)--C_(g) H_(2g) --CH₃,

(2) --C(R₅)(R₆)--Z--(Ph), or

(3) cis--CH₂ --CH═CH--CH₂ CH₃,

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph);

wherein (Ph) is phenyl or phenyl substituent by (T)s,

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇, wherein R₇ is alkyl of one to 4 carbon atoms,inclusive; and

wherein s is zero, one, 2 or 3, with the proviso that not more than twoT's are other than alkyl and when s is 2 or 3 the T's are either thesame or different;

wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, orα--CH₂ OH:β--H;

wherein R₆₀ is straight-chain alkyl of one to 6 carbon atoms, inclusive;and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

With regard to the divalent substituents described above, e.g., Q andW₁, these divalent radicals are defined as α--R_(i) :β--R_(j), whereR_(i) represents a substituent of the divalent moiety of the alphaconfiguration with respect to the cyclopentane ring and R_(j) representsa substituent of the divalent moiety of the beta configuration withrespect to the cyclopentane ring. Accordingly, when Q is defined asα--OH:β--R₈, the hydroxy of the Q moiety is in the alpha configuration,i.e. as in prostacyclin, and the R₈ substituent is in the betaconfiguration. Not all carbon atoms to which such divalent moieties areattached represent asymmetric centers. For example, when both valencebonds are to hydrogen (e.,g., W₁ or Q is α--H:β--H), then no asymmetriccenter is present.

I claim:
 1. A compound of the formula ##STR2## wherein L is (1)--(CH₂)_(d) --C(R₂)₂ --,(2) --CH₂ --O--CH₂ --Y--, or --CH₂CH═CH--,wherein d is zero to 5, R₂ is hydrogen, methyl or fluoro, beingthe same or different with the proviso that one R₂ is not methyl whenthe other is fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --;wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈, wherein R₈ ishydrogen or alkyl of one to 4 carbon atoms, inclusive;wherein R₄ is (1)--C(R₅)(R₆)--C_(g) H_(2g) --CH₃, (2) --C(R₅)(R₆)--Z--(Ph), or (3)cis--CH₂ --CH═CH--CH₂ CH₃,wherein C_(g) H_(2g) is alkylene of one to 9carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in thechain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ arehydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, beingthe same or different, with the proviso that one of R₅ and R₆ is fluoroonly when the other is hydrogen or fluoro and the further proviso thatneither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z representsan oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valencebond or alkylene of one to 9 carbon atoms, inclusive, with one to 6carbon atoms, inclusive between CR₅ R₆ -- and the (Ph); wherein (Ph) isphenyl or phenyl substituent by (T)s, wherein T is alkyl of one to 4carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇,wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero,one, 2 or 3, with the proviso that not more than two T's are other thanalkyl and when s is 2 or 3 the T's are either the same ordifferent;wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene,α--H:β--H, or α--CH₂ OH:β--H; wherein R₆₀ is straight-chain alkyl of oneto 6 carbon atoms, inclusive; and wherein X is (1) trans--CH═CH--, (2)cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --.